title: Naturally selected rilpivirine-resistant HIV-1 variants by host cellular immunity.
abstract: BACKGROUND
  Rilpivirine is listed as an alternative key drug in current antiretroviral therapy (ART) guidelines. E138G/A/K in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) are rilpivirine resistance-associated mutations and can be identified in a few ART-naive patients, although at low frequency. The 138th position in HIV-1 RT is located in one of the putative epitopes of human leukocyte antigen (HLA)-B*18-restricted cytotoxic T lymphocytes (CTLs). CTL-mediated immune pressure selects escape mutations within the CTL epitope. Here we tested whether E138G/A/K could be selected by HLA-B*18-restricted CTLs.
  
  
  METHODS
  The amino acid variation at the 138th position was compared between ART-naive HIV-1-infected patients with and without HLA-B*18. The optimal epitope containing the 138th position was determined and the impact of E138G/A/K on CTL response was analyzed by epitope-specific CTLs. The effect of E138G/A/K on drug susceptibility was determined by constructing recombinant HIV-1 variants.
  
  
  RESULTS
  The prevalence of E138G/A/K was 21% and 0.37% in 19 and 1088 patients with and without HLA-B*18, respectively (odds ratio, 72.3; P = 4.9 × 10(-25)). The CTL response was completely abolished by the substitution of E138G/A/K in the epitope peptide. E138G/A/K conferred 5.1-, 7.1-, and 2.7-fold resistance to rilpivirine, respectively.
  
  
  CONCLUSIONS
  E138G/A/K can be selected by HLA-B*18-restricted CTLs and confer significant rilpivirine resistance. We recommend drug resistance testing before the introduction of rilpivirine-based ART in HLA-B*18-positive patients.
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.forename: Hayato
authors.initials: H
authors.lastname: Murakoshi
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hachiya
authors.forename: Tsunefusa
authors.initials: T
authors.lastname: Hayashida
authors.forename: Takayuki
authors.initials: T
authors.lastname: Chikata
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Ode
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Wataru
authors.initials: W
authors.lastname: Sugiura
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D059911:HLA-B18 Antigen / Q000235:genetics / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008958:Models, Molecular; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D000068696:Rilpivirine; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D019380:Anti-HIV Agents; D018984:Epitopes, T-Lymphocyte; D059911:HLA-B18 Antigen; D009570:Nitriles; D011743:Pyrimidines; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000068696:Rilpivirine
keywords: CTL; E138G/A/K; HLA-B*18; rilpivirine